2,3-Benzodiazenines—Tofisopam
Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) is an exemplary 2,3-benzodiazepine molecule. Tofisopam is a non-sedative anxiolytic that has no appreciable sedative, muscle relaxant or anticonvulsant properties (Horvath et al., Progress in Neurobiology, 60 (2000), 309-342).
Tofisopam is a racemic mixture of (R)- and (S)-enantiomers. The chiral nature of tofisopam is due to the asymmetric carbon, at the 5-position of the benzodiazepine ring, attached with four different groups. Differential therapeutic effects have been noted for either cnantiomer. For example, the (R)-enantiomer of tofisopam has been isolated and shown to possess the nonsedative anxiolytic activity of the racemic mixture. See U.S. Pat. No. 6,080,736, the entire disclosure of which is incorporated herein by reference. Furthermore, the (R)-enantiomer has been shown to have a differential effect in the treatment of leukotriene B4-mediated disease. See U.S. Pat. No. 6,864,251, the entire disclosure of which is incorporated by reference. The (S)-enantiomer has been isolated and shown to possess an anticonvulsant activity. See U.S. Pat. No. 6,649,607; the entire disclosure of which is incorporated herein by reference. Similarly, the (S)-enantiomer has been shown to be effective in lowering body temperature, as in minimizing hot flashes. See US Patent Publication 2004/0229866, the entire disclosure of which is incorporated herein by reference.
Hyperuricemia
Hyperuricemia is a disease characterized by an abnormally high level of uric acid in the plasma. When the concentration of uric acid in the blood exceeds a certain level, uric acid precipitates as monosodium urate and may deposit in various tissues, such as the cavitas articulare or kidney. Hyperuricemia may be caused by reduced excretion of uric acid, by its excessive production, or by a combination of both. It may also result from other diseases, such as an enzymatic abnormality in purine metabolism. These are all so-called “primary cause” diseases. Examples of these “primary cause” diseases include gout (including acute gouty arthritis and chronic tophaceous arthritis), urinary calculus, hyperuricemic nephropathy (chronic gouty nephropathy, acute hyperuricemic nephropathy) and Lesch-Nyhan syndrome. Other diseases, such as disorders of the hemocytopoictic organs and renal disorders, and disorders resulting from the administration of a medicament, such as pyrazinamide or thiazide, may also result in hyperuricemia, and are typically referred to as “secondary cause” diseases. (See U.S. Pat. No. 6,353,009, herein incorporated by reference).
Gout is characterized by a disturbance of uric-acid metabolism occurring chiefly in males. Gout is characterized by painful inflammation of the joints, especially of the feet and hands, and arthritic attacks resulting from elevated levels of uric acid in the blood serum and the deposition of urate crystals around the joints. The condition can become chronic and result in deformity.
Gout can present another circumstance wherein it is known beforehand that an individual will or is likely to develop an inflammatory disorder. In the instance of patients undergoing radiotherapy or chemotherapy, the individual may experience a dramatic rise in serum uric acid levels associated with lysis of the tumor mass. Such large increases in uric acid can deposit urate crystals in synovial fluid of joints thereby causing the inflammatory disorder, gout. When such a rise in uric acid levels is known to be likely, prophylaxis with (S)-tofisopam can act to prevent the inflammatory condition of gout.
A number of treatments exist for hyperuricemia. However, none of these treatments have been totally efficacious in the treatment of hyperuricemia. The present invention provides a novel, effective method for the treatment of hyperuricemia.